(a) Field of the Invention
This invention relates to 2-substituted-4,5-dihydro-6-(pyridinyl)-3(2H)-pyridazinones, useful as cardiotonic agents, to their preparation, and to their use as cardiotonic agents.
(b) Description of the Prior Art
Haginiwa et al. [Yakugaku Zasshi 98 (1), 67-71 (1978); Chem. Abstrs. 88, 170,096v (1978)] reacted 3(2H)-pyridazinone with pyridine 1-oxide and platinized Pd-C catalyst to produce 6-(2-pyridinyl)-3(2H)-pyridazinone.
Yoshitomi Pharmaceutical Ind., Ltd. Japanese Patent Application Disclosure No. 19,987/79, published Feb. 15, 1979 and based on application No. 85,192/77, filed July 15, 1977, discloses, inter alia, the preparation of 4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone by refluxing for two hours an ethanolic solution of 3-(isonicotinoyl)propanoic acid [same as .gamma.-oxo-.gamma.-(4-pyridinyl)-butyric acid] and hydrazine hydrate. 4,5-Dihydro-6-(4-pyridinyl)-3(2H)-pyridazinone and closely related 4,5-dihydro-6-(4- or 3- or 2-pyridinyl)-5-R-3(2H)-pyridazinones, where R is H or lower alkyl, are said (page 2 of English translation) to be "useful not only as medicines such as hypotensive and anti-thrombus agents because they have pharmacological actions such as hypotensive, blood platelet coagulation-inhibitory and membrane-stabilizing actions, but also as intermediates for the synthesis of such medicines".
McEvoy and Allen [J. Org. Chem. 38, 4044-48 (1973); J. Med. Chem. 17, 281-286 (1974)] show a method for preparing 3-(substituted-benzoyl)-3-substituted-alkanoic acids and their reaction with hydrazine to prepare 6-(substituted-phenyl)-5-substituted-4,5-dihydro-3(2H)-pyridazinones, hypotensive agents.
Curran and Ross [J. Med. Chem. 17, 273-281 (1974)] show the preparation of 6-phenyl-4,5-dihydro-3(2H)-pyridazinones, hypotensive agents, by refluxing the requisite 3-benzoylpropionic acid with hydrazine hydrate in ethanol.
Albright, McEvoy and Moran [J. Heterocyclic Chem. 15, 881-892 (1978)] show the use of .alpha.-(substituted-phenyl)-4-morpholineacetonitriles in 1,4-additions to ethyl acrylate, ethyl crotonate, methyl .alpha.-methylacrylate, acrylonitrile, methylacrylonitrile, crotononitrile and cinnamonitrile to produce 4-cyano-4-(4-morpholinyl)-4-(substituted-phenyl)-butanenitriles and butanoic acid esters, and their conversion by reaction with hydrazine to 6-(substituted-phenyl)-4,5-dihydro-3(2H)-pyridazinones and, in turn, their dehydrogenation by reaction with bromine to produce 6-(substituted-phenyl)-3-(2H)-pyridazinones optionally bearing methyl at the 4- or 5-position of the pyridazinone ring.
McEvoy and Albright [J. Org. Chem. 44, 4597-4603 (1979)] show inter alia, the reaction of 2-cyano-2-(4- or 3-pyridinyl)-2-(4-morpholinyl) ethanenitrile with acrylonitrile or ethyl acrylate to produce respectively ethyl 4-cyano-4-(4- or 3-pyridinyl)-4-(4-morpholinyl)butanoate or 4-cyano-4-(4- or 3-pyridinyl)-4-(4-morpholinyl)butanenitrile.
Leete et al. [J. Org. Chem. 37, 4465-6 (1972)] shows the reaction of 2-(3-pyridinyl)-2-(4-morpholinyl)ethanenitrile with acrylonitrile to produce 4-cyano-4-(3-pyridinyl)-4-(4-morpholinyl)butanenitrile and its conversion by heating it with acetic acid, water and tetrahydrofuran to 4-oxo-4-(3-pyridinyl)butanenitrile.